Abstract
Introduction
Herpes simplex virus type 1 infection usually causes a mild, self-limiting painful blistering around the mouth, with 20% to 40% of adults affected at some time. Primary infection usually occurs in childhood, after which the virus is thought to remain latent in the trigeminal ganglion. Recurrence may be triggered by factors such as exposure to bright light, stress, and fatigue.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of interventions aimed at preventing recurrent attacks of herpes labialis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).
Results
At this update, searching of electronic databases retrieved 42 studies. After deduplication and removal of conference abstracts, 27 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 12 studies and the further review of 15 full publications. Of the 15 full articles evaluated, one systematic review and one RCT were added at this update. We performed a GRADE evaluation for six PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for three interventions based on information about the effectiveness and safety of oral antiviral agents, sunscreen, and topical antiviral agents.
Key Points
Herpes simplex virus type 1 infection usually causes a mild, self-limiting painful blistering around the mouth, with 20% to 40% of adults affected at some time.
Primary infection usually occurs in childhood, after which the virus is thought to remain latent in the trigeminal ganglion.
Recurrence may be triggered by factors such as exposure to bright light, stress, and fatigue.
The previous version of this overview examined the evidence on treating the first attack, as well as recurrent attacks of herpes labialis. This updated version of the overview looks at interventions aimed at preventing recurrent attacks.
We searched for evidence from RCTs and systematic reviews of RCTs in immunocompetent people.
Many of the RCTs we found were old (the majority published between 1985 and 2004), included different regimens and different populations (with different triggers for attacks), and were of limited methodological quality.
Prophylactic oral antiviral agents may reduce recurrent attacks compared with placebo, but we don't know the best timing and duration of treatment.
We found evidence that oral aciclovir and oral valaciclovir may be more effective than placebo.
However, we found no good evidence that oral famciclovir was effective, although evidence was limited to one RCT, which used artificial exposure to ultraviolet light to trigger attacks.
We don't know whether topical antiviral agents are beneficial as prophylaxis against recurrent attacks.
Most RCTs examined the effects of 5% topical aciclovir.
Sunscreen may reduce recurrent attacks; however, evidence is limited.
The evidence comes from two small crossover RCTs (57 people in total), both of which used artificial exposure to ultraviolet light to trigger attacks.
Clinical context
General background
Herpes labialis is a recurrent skin disease caused by re-activation of herpes simplex virus. Recurrence may be triggered by factors such as exposure to bright light, stress, and fatigue.
Focus of the review
An evidence-based review on the effects of preventative interventions is desirable. The interventions that are potentially useful in preventing herpes labialis, including oral and topical antiviral agents and sunscreens, were included in this overview.
Comments on evidence
We found one systematic review on the effects of oral antiviral agents, which included eight RCTs, and one systematic review on the effects of topical antiviral agents, which included three RCTs. We found most RCTs on the effects of oral aciclovir. We also found two RCTs on the effects of sunscreen. We found few recently published RCTs. Factors affecting the generalisability of the results to clinical practice included use of a non-proprietary preparation in one trial, regimens and included populations that varied widely between included RCTs, and, in some RCTs, use of artificial exposure to ultraviolet light to produce recurrence of lesions.
Search and appraisal summary
The update literature search for this review was carried out from the date of the last search, February 2009, to November 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 42 studies. After deduplication and removal of conference abstracts, 27 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 12 studies and the further review of 15 full publications. Of the 15 full articles evaluated, one systematic review and one RCT were added at this update.
About this condition
Definition
Herpes labialis is a mild, self-limiting infection with herpes simplex virus type 1 (HSV-1). It causes pain and blistering on the lips and perioral area (cold sores); fever and constitutional symptoms are rare. Most people have no warning of an attack, but some experience a recognisable prodrome. In this overview, we have included studies in people with normal immunity and excluded studies in people who are immunocompromised (e.g., studies in people with HIV or with cancer undergoing chemotherapy).
Incidence/ Prevalence
Herpes labialis accounts for about 1% of primary care consultations in the UK each year. One study showed an annual prevalence of 17%, while 20% to 40% of people have experienced cold sores at some time during their lifetime.
Aetiology/ Risk factors
Herpes labialis is caused by HSV-1. After the primary infection, which usually occurs in childhood, the virus is thought to remain latent in the trigeminal ganglion. A variety of factors, including exposure to bright sunlight, fatigue, psychological stress, fever, menstruation, or trauma to the area of primary infection can precipitate a recurrence.
Prognosis
In most people, herpes labialis is a mild, self-limiting illness. Recurrences are usually shorter and less severe than the initial attack. Healing is usually complete in 7 to 10 days without scarring. Rates of re-activation are unknown. Herpes labialis can cause serious illness in immunocompromised people.
Aims of intervention
To reduce the frequency and severity of recurrent attacks; to speed healing of lesions; to reduce pain, with minimal adverse effects.
Outcomes
Rate of recurrence; symptom improvement (severity of symptoms and duration of symptoms; does not include time to healing or crusting of lesions); time to healing (time to healing/time to crusting of lesions); quality of life; adverse effects.
Methods
Search strategy BMJ Clinical Evidence search and appraisal date November 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to November 2014, Embase 1980 to November 2014, The Cochrane Database of Systematic Reviews November 2014, issue 11 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributor. In consultation with the expert contributor, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section (see below). Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributor may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update we have removed the following previously reported questions: what are the effects of antiviral treatments for the first attack of herpes labialis? what are the effects of treatments for recurrent attacks of herpes labialis? Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Herpes labialis.
| Important outcomes | Quality of life, Recurrence, Symptom improvement , Time-to-healing | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of interventions aimed at preventing recurrent attacks of herpes labialis? | |||||||||
| 8 (933) | Recurrence | Prophylactic oral antiviral agents versus placebo | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for weak methods; consistency point deducted for significant statistical heterogeneity; directness point deducted for experimental exposure to artificial ultraviolet light and differences between RCT affecting generalisability (triggers used, regimens used) |
| 1 (243) | Time-to-healing | Prophylactic oral antiviral agents versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and use of experimental exposure to artificial ultraviolet light |
| 4 (350) | Recurrence | Topical antiviral agents versus placebo | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for weak methods and incomplete reporting of results; directness points deducted for experimental exposure to artificial ultraviolet light, different regimens between different RCTs, and use of a non-proprietary preparation |
| 2 (at least 90) | Symptom improvement | Topical antiviral agents versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for weak methods, sparse data, and incomplete reporting of results; directness point deducted for experimental exposure to artificial ultraviolet light |
| 1 (90) | Time-to-healing | Topical antiviral agents versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for experimental exposure to artificial ultraviolet light |
| 2 (57) | Recurrence | Sunscreen versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and short follow-up; directness point deducted for use of experimental exposure to artificial ultraviolet light |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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